Modified Project Summary/Abstract Section Malfunction of peripheral T cells is associated with impaired learning, changes in social behaviors and reduced neurogenesis. Reconstitution of immune deficient recipients with T cells from wild type donors restores these brain functions. T cells mediate their beneficial effects on the brain through meningeal spaces, which are closely associated with peripheral immunity through the meningeal lymphatic vessels. It has also been demonstrated that chronic stress is correlated with gut inflammation and with impairments in learning and neurogenesis. We have addressed, at least partially, what type of immune cells are mediating neuro-immune interactions (T cells), and where (meningeal spaces), although how the changes in peripheral immunity as a result of stress are impacting the brain has not yet been addressed. Based on our new data, we aim to provide novel insights into these complex interactions. Our overarching hypothesis is that changes in the gut microbiota as a result of stress facilitate changes in the immune composition of the deep cervical lymph nodes, which are reflected in meningeal immunity, which in turn impacts brain function, thus creating a tripartite loop: brain-immune-gut. In this proposal, we will address how metabolites of the kynurenine pathway, found to be dysregulated during chronic mild stress by the gut microbiome, affect T cell function in the meningeal spaces, and how these immune changes impact brain function. Our results suggest that gut microbiota could be targeted therapeutically to mitigate abnormal immune changes during chronic stress, which in turn would protect the brain.?